1,3-dihydro-1 oxophosphinylalkyl-2h-1,4-benzodiazepine-2-ones

ABSTRACT

OXO-PHOSPHINYL-BENZODIAZEPINES ARE DISCLOSED WHICH HAVE TRANQUIILIZING PROPERTIES AND ARE SUITABLE FOR ENTERAL OR PARENTERAL ADMINISTRATION.

United States Patent 3,738,982 1,3-DIHYDRU-1 OXOPHOSPI-IINYLALKYL-ZH-1,4-IIENZODIAZEPINE-2-0NES Erhard Wolf, Hofheim, Taunus, Hans Kohl,Schwalbach, Taunus, and Gunter Hartfelder, Frankfurt am Main, Germany,assignors to Farbwerke Hoechst Aktien-" gesellschaft vormals MeisterLucius & Bruning, Frankfurt am Main, Germany No Drawing. Filed May 6,1971, Ser. No. 140,977 Claims priority, application Germany, May 8,1970, P 22 503.0; Sept. 23, 1970,P 20 46 848.8 Int. Cl. C07d 53/06 US.Cl. 260239.3 D 9 Claims ABSTRACT OF THE DISCLOSUREOxo-phosphinyl-benzodiazepines are disclosed which have tranquilizingproperties and are suitable for enteral or parenteral administration.

The present invention relates to benzodiazepines and to a process forpreparing them.

More particularly, the invention relates to derivatives ofbenzodiazepines of the general Formula I in which R and R which may beidentical or different, each represent a hydrogen atom, a nitro group, ahalogen atom or the trifluoromethyl group and R in addition mayrepresent a straight chain or branched alkyl group having 1 to 6 carbonatoms, R represents a straight chain or branched alkyl group having 1 to3 carbon atoms, and n is a number from 1 to 6.

The invention furthermore provides a process for preparing theabove-specified compounds, which comprises either reactingbenzodiazepine derivatives of the general Formula II in which Mrepresents a metal cation and R and R have the meanings given above,with oxophosphine compounds of the general Formula III in which R hasthe meaning given above and X represents a halogen atom or the radicalof an alkane-sulfonic or aryl-sulfonic acid, or reactingo-aminobenzophenones of the general Formula IV 3,738,982 Patented June12, 1973 in which R R R and n have the meanings given above, withderivatives of amino-acetic acid, preferably with the esters thereof, orfirst reacting the compounds of Formula IV with halides ofhalogenoacetic acid, then with ammonia and eventually cyclizising thecompounds so obtained.

As benzodiazepines which may be used in the process of the invention andmay be prepared according to known processes there may be mentioned, byway of example:

7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2- The correspondingphosphine-oxides, for example chloromethyl-dimethyl-phosphine-oxide,bromomethyl-dimethyl-phosphine-oxide,Z-chloroethyl-dimethyl-phosphine-oxide,3-chloro-propyl-dimethylphosphine-oxide,iodomethyl-dimethyl-phosphine-oxide, methane-sulfonicacid-dimethyl-oxo-phosphinyl-methyl ester, p-toluene-sulfonicacid-dimethyl-oxo-phosphinyl-methyl ester,

can also be obtained according to known processes, even theafore-mentioned compounds in which the term dimethy is replaced bydiethyl, dipropyl or diisopropyl.

The conversion of the lH-benzodiazepines into the corresponding metalcompounds, preponderantly alkali metal compounds, can be carried outaccording to known methods, for example by heating with calcium hydride,sodium hydride, lithium hydride, potassium tert. butylate, sodiummethylate, etc. For this purpose, the use of organic solvents is ofadvantage.

Depending on the reactivity of the phosphorus component, the reactionaccording to the invention is preferably carried out at elevatedtemperatures, approximately between room temperature and 200 C. It isadvantageous to carry out the reaction in a solvent at the boilingtemperature of this solvent. However, the reaction may also be effectedin the absence of a solvent.

As solvents for the formation of the metal compound as well as for thereaction with the phosphorus compound, inert solvents, for exampletoluene, xylene, dimethylformamide, dimethylacetamide, tetrahydrofurane,dioxane or acetonitrile may be used. It is especially advantageous toprepare the compounds of the invention directly after the formation ofthe metal salts, without isolating the latter, in the same reactionvessel.

Furthermore, it is possible to prepare oxo-phosphinebenzodiazepines fromcorrespondingly substituted aminobenzophenones by reaction withderivatives of aminoacetic acid derivatives, for example with the iminoesters, the ortho esters, preferably with amino-acetic acid esters,according to the following reaction scheme:

0 mai (Rs):

NC=O

R1 /CH,,

in which R represents an alkyl or aryl group; in this case, the reactionis carried out according to known methods. Under certain circumstances,it may also be of advantage to effect cyclization according to thefollowing reaction scheme:

i (S m-Eula):

XiCOCHzXz R;

H )n a)z CHzX NH: R1

0 O N-C? /NC HNH R; C 2 a Pyridine R; CH:

R2 R l wherein X and X represent a halogen atom and X in addition mayrepresent the azido group N Cyclization may be effected, for example inpyridine.

The process of the present invention permits the synthesis of hithertounknown benzodiazepines which contain the oxo-phosphine grouping andwhich are distinguished by favourable hydrophilic properties. Thus, byusing suitable phosphorus components it is possible to vary within widelimits the ratio of distribution between water and lipoids. For example,it is thus possible to prepare compounds which are easily soluble inwater and which are stable in aqueous systems also at elevatedtemperatures.

Since the known minor tranquillizers diazepam (7- chloro-1,3 dihydro 1methyl-S-phenyl-ZH-1,4-benzodiazepine-Z-one) andmeprobamate(2,2-di-(carbamoyloxymethyl)-pentane) are not water-solubleand chlorodiazepoxide (7-chloro-2-methylamino 5 phenyl-3H-1,4-benzodiazepine-4-oxide) is not stable in aqueous solution, awater-soluble, chemically stable substance of the type of diazepamrepresents an important therapeutical progress. All of the products ofthe invention show a very good to sufiiciently good solubility in waterand have a strong protecting action against clonic persistentconvulsions and maximum tonic seizures after metrazole infusion in mice(Bastian et al., J. of Pharmacol., 127, 75 (1959)) and against theprovoked electrically maximum extensor seizure in the mouse. Inaddition, the compounds have a potentiating effect on the narcosisproduced by hexobarbital in the mouse.

Even when administered perorally, the compounds of the invention have astrong activity. In addition, they show very favourable data with regardto the acute toxicity. The good solubility of the compounds in waterpermits their intravenous administration without using a solubilizer. Itis surprising, that the introduction of the dialkyl-oxophosphinegrouping causes such a good solubility in water in the stronglyhydrophobic benzodiazepine molecule and that the tranquillizingproperties are maintained and the toxicity is even markedly reduced.

The compounds of the present invention may be used as medicaments in theform of pharmaceuetical prepara tions which are suitable for enteral orparenteral application. The preparations may be in solid form, forexample in the form of tablets, dragees, suppositories, capsules or inliquid form, above all in the form of aqueous solutions. If desired,they may contain the usual adjuvants and excipients or conservingagents, stabilizers, etc. They may also contain other therapeuticallyvaluable substances.

The following examples illustrate the invention.

EXAMPLE 1 (a) 30.5 g. (0.11 mole) of 7-chloro-1,3-dihydro-5-phenyl-ZH-1,4-benzodiazepine-2-one were dissolved in 200 ml. of absolutexylene and combined with 5 g. 0.11 mole) of sodium hydride (about 55% inparaflin oil). After having boiled the whole for 5 hours under reflux,13 g. (0.13 mole) of chloromethyl-dimethylphosphine-oxide, dissolved in50 ml. of absolute xylene, were added to the reaction mixture and themixture was heated to the boiling temperature for 3 hours, whilestirring. The reaction mixture was then allowed to stand overnight atroom temperature. Undissolved matter was then filtered oflf with suctionwhile hot, the residue was washed with hot xylene. After concentrationof the filtrate under reduced pressure, the residue was freed fromresidual solvent by steam distillation, filtered with suction overactive charcoal and washed thoroughly with hot water. The filtrate wasevaporated to dryness under reduced pressure and residual amounts ofwater were removed by boiling of the residue in toluene in a waterseparator. Exhaustive extraction in a Soxhlet apparatus of the residuewith cyclohexane and following recrystallization of the cyclohexaneextract from yle e y ded 21- gf co p und (=5-2-% of heo y),

The melting point was at 174-175 C. and 193-195 C., respectively,depending on the respective crystal modification. The 7-chloro1,3-dihydro-1-dimethyl-oxophosphinylmethyl-5-phenyl-2H-1,4-benzodiazepine-2-onewas found to have a very good solubility in water already at roomtemperature. The structure of the compound was proved by IR (infrared)-,NMR (nuclear magnetic resonance)- and MS (mass)- spectrometry.

C H ClN O P (360.5) Calcd. (percent): C, 60.0; H, 5.0; Cl, 9.9; N, 7.8.;P, 8.6. Found (percent): C, 59.8; H, 5.1; C1, 9.7; S, 8.0; P, 8.4.

(b) 50 g. (0.185 mole) of7-chlor0-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine were stirred at 40C. into a solution of 27.5 g. (0.22 mole) ofchloromethyl-dimethylphosphine-oxide in 340 ml. of anhydrous benzeneand. after about 5 minutes, 8.5 g. (0.195 mole) of sodium hydride (about55% in parafiin oil) were added portionwise, while stirring, in such amanner that the temperature did not exceed 55 C. The reaction mixturewas then slowly heated to the boiling temperature and boiled for 4 hoursunder reflux. From the reaction solution, which had been filtered,optionally with addition of silica gel, there crystallized, afterstorage for several hours at room temperature, the main quantity of the7-chloro-1,3-dihydro-1-dimethyl-oxo-phosphinyl-methyl-S-phenyl-2H 1,4benzodiazepine-Z-one; a further proportion could be isolated from themother liquor. After recrystallization from acetone, a total of 53.5 g.(80% of the theory) of colorless crystals melting at 193195 C. wasobtained.

(c) 20 g. (0.074 mole) of7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one were dissolvedin 150 ml. of dimethylformamide and combined with 4 g. of sodium hydride(about 55% strength in paraffin oil) (0.092 mole). The reaction mixturewas stirred for 1 hour at 50 C. and the sodium salt that had formed wascombined with 18 g. (0.097 mole) of methane-sulfonicacid-dimethyl-oxophosphinyl-methyl ester. After heating for 5 hours to70 C., the reaction was almost quantitative. The solvent was removedunder reduced pressure and working up was carried out as describedabove. The same compound was obtained in a yield of 60% and was found tocorrespond with all of its physical data with the substance preparedfrom chloromethyl-dimethyl-phosphine-oxide.

(d) The substance was furthermore prepared by reaction of 5chloro-Z-(N-dimethyl-oxophosphinylmethyl)- amino-benzophenone (meltingpoint 137138 C. (from cyclohexane) with glycine-ester hydrochloride orby reaction with bromoacetyl bromide, following amination in liquidammonia and condensation in pyridine.

For isolating and purifying the compounds of the invention,chromatography on silica gel was used with success, whereby the yieldswere in general considerably improved.

EXAMPLE 2 27 g. (0.1 mole) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one were dissolved in 150 ml. of absolute Xyleneand combined with 5 g. (0.11 mole) of sodium hydride (about 55% strengthin paraffin oil). After having boiled the whole for 5 hours underreflux, 17.5 g. (0.12 mole) of chloro-ethyl-dimethyl-phosphine-oxide,dissolved in 50 ml. of absolute xylene, were added dropwise to thereaction mixture and the whole was heated for 3 hours to the boilingtemperature, while stirring. Working up of the reaction mixture waseffected as described in Example 1. From a mixture of ligroine andxylene 1:1), there crystallized 15.8 g. (42% of the theory) of7-chloro-1,3-dihydro-l-dimethyl-oxophosphinylethyl-S-phenyl-ZH-1,4-benzodiazepine-2-one in the form of an easilywater-soluble compound melting at 170-175 C. The structure of thecompound was proved by IR-, NMR- and MS-spectrography.

C H ClN O P (374.5) Calcd. (percent): C, 60.8; H, 5.3; Cl, 9.5; N, 7.5;P, 8.3. Found (percent): C, 61.1; H, 5.5; CI, 9.4; N, 7.4; P, 8.0.

6 EXAMPLE 3 4.4 g. (0.1 mole) of sodium hydride (about 55% strength inparafiin oil) were added to 24 g. (0.089 mole) of7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine- 2-one in 400 ml. ofabsolute toluene and the whole was boiled for 15 hours under reflux.After addition of 15 g. (0.097 mole) of3-chloropropyl-dimethyl-phosphineoxide, the whole was stirred forfurther 8 hours under reflux, while stirring, and the sodium chloridethat had precipitated was then filtered off. The solvent was removedunder reduced pressure and the residue was stirred with 250 ml. of 50 C.hot water. The filtered aqueous solution Was then treated with activecharcoal. The benzodiazepine of the invention was isolated by exhaustiveextraction with ethyl acetate. After drying over sodium sulfate, thes0lvent was removed by distillation under reduced pressure. Uponstanding, the 7-chloro-1,3-dihydro-l-dimethyl-oxophosphinyl-n-propyl 5phenyl-ZH-1,4-benzodiazepine-2- one (16 g.=47% of the theory)crystallized. For purification, the compound which was found to besoluble in Water was recrystallized from a mixture of benzene andcyclohexane (1: 1). The structure of the compound, which was found tomelt at 154 C., was proved by the data obtained by IR-, NMR- andMS-spectroscopy.

C20H22C1N202P (38 8.5) Calcd. (percent): C, 61.7; H, 5.6; P, 7.98. Found(percent): C, 61.5; H, 5.6; P, 7.8.

EXAMPLE 4 30.5 g. of 7-chloro-l,3-dihydro-5,2'-chlorophenyl-2H-1,4-benzodiazepine-2-one (0.1 mole) were dissolved in 200 ml. ofabsolute xylene and combined with 5 g. (0.11 mole) of sodium hydride(about 55% strength in paraffin oil). After having boiled the whole -for5 hours under reflux, 13 g. (0.1 mole) ofchloromethyl-dimethylphosphine-oxide in 50 ml. of absolute xylene wereadded to the reaction mixture and the mixture was heated to the boilingtemperature for 3 hours, while stirring. The reac tion mixture was thenallowed to stand overnight at room temperature. Working up of thereaction mixture was effected as described in Example 1.

Instead of the chloromethyl-dirnethyl-phosphine-oxide, thebromomethyl-dimethyl-phosphine-oxide was used with the same success. Thephysical data obtained by analysis undoubtedly indicated the structuureof the 7- chloro 1,3-dihydro 1 dimethyloxophosphinyImethyI-S- 2chlorophenyl-ZH-l,4-benzodiaZepine-2-one. Melting point 240 C. (withdecomposition). Yield: 15 .8 g. (40% of the theory). The compound wasfound to be only sparingly soluble at room temperature, but easilysoluble in water 40-50 C.

C H Cl N O P (395) Calcd. (percent): C, 54.7; H, 4.3; Cl, 18.0; P, 7.9.Found (percent): C, 54.4; H, 4.5; Cl, 18.2; P, 7.8.

EXAMPLE 5 19 g. (0.061 mole) of7-chloro-l,3-dihydro-5-4'-isopropylphenyl 2H 1,4-benzodiazepine 2 onewere dissolved in 200 ml. of absolute xylene and combined with 3.1 g.(0.068 mole) of sodium hydride (about 55% strength in parafiin oil).After having boiled the whole for 5 hours under reflux, 9 g. (0.09 mole)of chloromethyl-dimethyl-phosphine-oxide in 30 ml. of absolute xylenewere added and the mixture was heated for 3 hours to the boilingtemperature. The reaction mixture was then allowed to stand overnight atroom temperature and worked up as described in Example 1. The yield of7-chloro-1,3-dihydro-1-dimethyl-oxophosphinylmethyl- 5-4'isopropylphenyl-ZH-1,4-benzodiazepine-2-one was 11 g. (45% of thetheory). Melting point: -153 C. At 40-50 C., the compound was found tobe easily soluble in water.

C H ClN O P (402.5) Calcd. (percent): C, 62.5; H, 6.0; Cl, 8.8; N, 7.0;P, 7.7. Found (percent): C, 62.3; H, 5.8; CI, 8.6; N, 6.8; P, 7.5.

7 EXAMPLE 6 7-chlorol ,3 -dihydro-1- (diethyl-oxophosphinylmethyl)-S-phenyl-ZH-1,4-benzodiazepine-2-one 27 g. (0.1 mole) of 7 chloro 1,3dihydro-S-phenyl- 2H-l,4-benzodiazepine-2- one were stirred for hoursunder reflux in 200 ml. of absolute xylene with 5 g. (0.11 mole) ofsodium hydride (about 55% in paraflin oil). The reaction mixture wascooled and 22 g. (0.11 mole) of bromomethyl-diethyl-phosphineoxide,dissolved in 100 ml. of hot absolute xylene were added thereto dropwise.The reaction mixture was then stirred for 3 hours under reflux. The hotsolution was filtered, the NaBr was separated by filtration and washedwith hot toluene and the combined filtrates were concentrated as far aspossible. The residue was dissolved in hot water, the solution wasclarified with active charcoal and the water was removed by distillationunder reduced pressure. Residual traces of humidity were eliminated byboiling with toluene on a water separator. The toluene was removed bydistillation and the residue was recrystallized from xylene. 17.6 g. ofthe above-specified compound were obtained, which was found to melt at178-180 C. (45% of the theory).

C H ClN O P (388.5) Calcd. (percent): C, 61.7; H, 5.7; N, 7.2; P, 8.0.Found (percent): C, 61.5; H, 5.9; N, 7.4; P, 7.8.

EXAMPLE 7 7-chloro-1,3-dihydro-1- (diethyl-oxophosphinylmethyl)5-(4'-isopropyl)-phenyl-2H-1,4-benzodiazepine-2-one 31 g. (0.1 mole) of7-chloro-1,3-dihydro-4,4-isopropylphenyl-2H-1,4-benzodiazepine-2-onewere stirred for 5 hours under reflux in 200 ml. of absolute xylene with5 g. (0.11 mole) of sodium hydride (about 55% strength in paraflin oil).The reaction mixture was slightly cooled and then 22 g. (0.11 mole) ofbromomethyldiethyl-phosphine oxide, dissolved in 100 ml. of hot absolutexylene, were added thereto dropwise. After further stirring for 3 hoursunder reflux, undissolved matter was filtered off, the residue waswashed with hot toluene and the combined filtrates were concentratedunder reduced pressure. The residue was dissolved in absolute benzeneand purified over a column of silica gel. As eluant, methylene chloridewith increasing quantities of acetone was used. After removal of theeluant by distillation under reduced pressure, the residue was dissolvedin hot petroleum ether and clarified with active charcoal. The petroleumether was removed by distillation under reduced pressure, whereupon 45g. of the above-specified compound were obtained in the form of anon-distillable oil.

C I-I ClN O P (430.5) Calcd. (percent): C, 61.7, H, 5.7; N, 7.2; P, 8.0.Found (percent): C, 61.5; H, 5.7; N, 7.4; P, 8.3.

EXAMPLE 8 7 chloro-1,3-dihydro-1-(di n propyl oxophosphinylmethyl) 5(2'-chloro) phenyl 2H 1,4 benzodi azepine-Z-one 13 g. (0.043 mole) of7-chloro-1,3-dihydro-5-2-chlorophenyl-2H-1,4-benzodiazepine 2 one wereheated for 6 hours, while stirring mechanically during the whole time,in 250 ml. of boiling xylene with 2.6 g. of sodium hydride (55 strengthin parafiin oil) (0.06 mole). The suspension was cooled to 60 C. andthen 13.5 g. (0.056 mole) of methanesulfonylmethyl din-propyl-phosphine-oxide were added dropwise. The mixture was thenstirred for 13 hours under reflux, the reaction solution was separatedby filtration from the sodium salt that had precipitated andconcentrated under reduced pressure. The product was isolated afteraddition of 100 ml. of water by thorough shaking with ethyl acetate. Theethyl acetate phase was dried over sodium sulfate. After removal of theorganic solvent, 16 g. of the above-specified compound of the theory)were obtained; the analytically pure compound was obtained afterrecrystallization from xylene and showed a melting point of 157-160 C.

C22H25C12N202P1 Calc. (percent): C, H, 5.6; CI, 15.7; N, 6.2; P, 6.8.Found (percent): C, 58.5; H, 5.8; Cl, 15.55; N, 6.1; P, 6.7.

We claim:

1. A compound of the Formula I in which R and R which may be identicalor different, each represent a hydrogen atom, a nitro group, a halogenatom or the trifluoromethyl group and R in addition may represent astraight chain or branched alkyl group having 1 to 6 carbon atoms, Rrepresents a straight chain or branched alkyl group having 1 to 3 carbonatoms, and n is a number from 1 to 6.

2. The compound defined in claim 1 which is 7-chloro-1,3-dihydro-1-dimethyl-oxophosphinylmethyl 5 phenyl-2H-1,4-benzodiazepine-2-one.

3. The compound defined in claim 1 which is 7-chloro- 1,3dihydro-1-dimethyl-oxophosphinylethyl 5 phenyl-2H-1,4-benzodiazepine-2-one.

4. The compound defined in claim 1 which is 7-chloro-1,3-dihydro-l-dimethyl-oxophosphinyl npropyl-S-phenyl-2H-1,4-benzodiazepine-2-one.

5. The compound defined in claim 1 which is 7-chloro- 1,3-dihydro 1dimethyl-oxophosphinylmethyl 5 (2'-chlorophenyl)-2H-1,4-benzodiazepine-2-one.

6. The compound defined in claim 1 which is 7-chloro-1,3-dihydro-1-dimethyl-oxophosphinylmethyl 5 (4'-isopropylphenyl)-2H-1,4-benzodiazepine-2-one.

7. The compound defined in claim 1 which is 7-ch1oro-1,3-dihydro-1-diethyl-oxophosphinylmethyl 5 phenyl-2H-1,4-benz0diazepine-2-one.

8. The compound defined in claim 1 which is 7-ch1oro-1,3-dihydro-l-diethyl-oxophosphinylmethyl 5 (4' -iso propylphenyl)-2H-1,4-benzodiazepine-2-one.

9. The compound defined in claim 1 which is 7-chloro-1,3-dihydro-1-di-n-propyl-oxophosphinylmethyl 5 (2'-chlorophenyl)-2H-1,4-benzodiazepine-2-one.

References Cited UNITED STATES PATENTS 3,371,085 2/1968 Reeder et a1.260239.3 D

HENRY R. JI-LES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl.X.R.

424-244; 260570 AB, 606.5 P, 562 B, 562 N

